Antoine Muchir1, Wei Wu2, Fusako Sera3, Shunichi Homma3, Howard J Worman4. 1. Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY, USA. Electronic address: a.muchir@institut-myologie.org. 2. Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY, USA. 3. Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA. 4. Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY, USA. Electronic address: hjw14@columbia.edu.
Abstract
BACKGROUND: Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of Lmna(H222P/H222P) mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in Lmna(H222P/H222P) mice and assessed if adding a MEK1/2 inhibitor would provide added benefit. METHODS: Male Lmna(H222P/H222P) mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated. RESULTS: Treatment of Lmna(H222P/H222P) mice with either benazepril or selumetinib started at 8weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left ventricular fractional shortening at 20weeks of age. CONCLUSIONS: Both ACE inhibition and MEK1/2 inhibition have beneficial effects on left ventricular function in Lmna(H222P/H222P) mice and both drugs together have a synergistic benefit when initiated after the onset of left ventricular dysfunction. These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor in addition to standard of care in patients with dilated cardiomyopathy caused by LMNA mutations.
BACKGROUND: Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of Lmna(H222P/H222P) mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in Lmna(H222P/H222P) mice and assessed if adding a MEK1/2 inhibitor would provide added benefit. METHODS: Male Lmna(H222P/H222P) mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated. RESULTS: Treatment of Lmna(H222P/H222P) mice with either benazepril or selumetinib started at 8weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left ventricular fractional shortening at 20weeks of age. CONCLUSIONS: Both ACE inhibition and MEK1/2 inhibition have beneficial effects on left ventricular function in Lmna(H222P/H222P) mice and both drugs together have a synergistic benefit when initiated after the onset of left ventricular dysfunction. These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor in addition to standard of care in patients with dilated cardiomyopathy caused by LMNA mutations.
Authors: G Bonne; E Mercuri; A Muchir; A Urtizberea; H M Bécane; D Recan; L Merlini; M Wehnert; R Boor; U Reuner; M Vorgerd; E M Wicklein; B Eymard; D Duboc; I Penisson-Besnier; J M Cuisset; X Ferrer; I Desguerre; D Lacombe; K Bushby; C Pollitt; D Toniolo; M Fardeau; K Schwartz; F Muntoni Journal: Ann Neurol Date: 2000-08 Impact factor: 10.422
Authors: Matthew R G Taylor; Pamela R Fain; Gianfranco Sinagra; Misi L Robinson; Alastair D Robertson; Elisa Carniel; Andrea Di Lenarda; Teresa J Bohlmeyer; Debra A Ferguson; Gary L Brodsky; Mark M Boucek; Jean Lascor; Andrew C Moss; Wai Lun P Li; Gary L Stetler; Francesco Muntoni; Michael R Bristow; Luisa Mestroni Journal: J Am Coll Cardiol Date: 2003-03-05 Impact factor: 24.094
Authors: D Fatkin; C MacRae; T Sasaki; M R Wolff; M Porcu; M Frenneaux; J Atherton; H J Vidaillet; S Spudich; U De Girolami; J G Seidman; C Seidman; F Muntoni; G Müehle; W Johnson; B McDonough Journal: N Engl J Med Date: 1999-12-02 Impact factor: 91.245
Authors: A Muchir; G Bonne; A J van der Kooi; M van Meegen; F Baas; P A Bolhuis; M de Visser; K Schwartz Journal: Hum Mol Genet Date: 2000-05-22 Impact factor: 6.150
Authors: Jop H van Berlo; Willem G de Voogt; Anneke J van der Kooi; J Peter van Tintelen; Gisèle Bonne; Rabah Ben Yaou; Denis Duboc; Tom Rossenbacker; Hein Heidbüchel; Marianne de Visser; Harry J G M Crijns; Yigal M Pinto Journal: J Mol Med (Berl) Date: 2004-11-13 Impact factor: 4.599
Authors: Eloisa Arbustini; Andrea Pilotto; Alessandra Repetto; Maurizia Grasso; Andrea Negri; Marta Diegoli; Carlo Campana; Laura Scelsi; Elisa Baldini; Antonello Gavazzi; Luigi Tavazzi Journal: J Am Coll Cardiol Date: 2002-03-20 Impact factor: 24.094
Authors: G Bonne; M R Di Barletta; S Varnous; H M Bécane; E H Hammouda; L Merlini; F Muntoni; C R Greenberg; F Gary; J A Urtizberea; D Duboc; M Fardeau; D Toniolo; K Schwartz Journal: Nat Genet Date: 1999-03 Impact factor: 38.330
Authors: Can Zhou; Chen Li; Bin Zhou; Huaqin Sun; Victoria Koullourou; Ian Holt; Megan J Puckelwartz; Derek T Warren; Robert Hayward; Ziyuan Lin; Lin Zhang; Glenn E Morris; Elizabeth M McNally; Sue Shackleton; Li Rao; Catherine M Shanahan; Qiuping Zhang Journal: Hum Mol Genet Date: 2017-06-15 Impact factor: 6.150